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Observation |

Multiple Epithelioid Spitz Nevi or Tumors With Loss of BAP1 Expression A Clue to a Hereditary Tumor Syndrome FREE

Klaus J. Busam, MD; Michelle Wanna, MD; Thomas Wiesner, MD
[+] Author Affiliations

Author Affiliations: Department of Pathology (Dr Busam) and Human Oncology and Pathogenesis Program (Dr Wiesner), Memorial Sloan-Kettering Cancer Center, New York, New York; and Avera Medical Group Dermatology, Sioux Falls, South Dakota (Dr Wanna).


JAMA Dermatol. 2013;149(3):335-339. doi:10.1001/jamadermatol.2013.1529.
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Published online

ABSTRACT

Importance Recently, a group of melanocytic tumors with loss of BAP1 expression has been described. The lesions may occur sporadically or as part of a familial cancer syndrome. They have distinct histopathologic features characterized by a nevuslike silhouette and cytologic composition of large epithelioid melanocytes with oval vesicular nuclei, distinct nucleoli, and abundant cytoplasm. The large melanocytes are immunohistochemically characterized by loss of nuclear labeling for BAP1.

Observations We describe a 21-year-old patient with multiple combined melanocytic proliferations composed of both a nevus component with strong BAP1 expression and a large epithelioid melanocyte population with loss of BAP1 expression. The occurrence of multiple BAP1loss melanocytic lesions raised concerns about a possible germline mutation. Sequence analysis of DNA from lesional and nonlesional skin confirmed a BAP1 germline mutation.

Conclusions and Relevance The presence of multiple clinically banal–appearing melanocytic lesions with childhood onset suggests that the combined lesions with BAP1loss large epithelioid melanocytes described herein are probably combined nevi. Our findings also illustrate how the detection of a histopathologically distinct melanocytic lesion, coupled with knowledge of its possible association with a hereditary tumor syndrome, can lead to the suspicion and confirmation of a germline mutation.

Figures in this Article

The distinction of Spitz nevi or tumors from melanoma and the nature of spitzoid melanocytic proliferations with features intermediate between a nevus and melanoma (so-called atypical Spitz tumors) represent a known problem area in dermatopathology.15 Recently, a morphologically distinct variant in the spectrum of Spitz nevi or tumors has been associated with BRAFV600E (Online Mendelian Inheritance in Man [OMIM] 164757) mutations and loss of BAP1 (OMIM 603089) expression.6,7 First, an autosomal dominant tumor syndrome caused by inactivating germline mutations of the BAP1 gene was described.7 Affected individuals developed multiple skin-colored, dome-shaped, well-circumscribed papules, which were histopathologically composed of large epithelioid melanocytes.

The melanocytes lacked immunohistochemical expression of BAP1 due to loss of the remaining wild-type BAP1 allele by various somatic alterations. Subsequently, morphologically similar melanocytic tumors were recognized in a sporadic setting (ie, in patients lacking germline mutations).6 The sporadic lesions show loss of BAP1 expression, but in contrast to most Spitz nevi,810 they tend to harbor BRAFV600E mutations. Preliminary evidence suggests that most of these lesions are clinically indolent.

We report a case of multiple combined BAP1loss/BRAFV600E melanocytic lesions. The case has novel aspects, namely, the presence of multiple combined BAP1loss lesions in one patient and documentation that the lesions have been present since childhood. The case also illustrates that, once an association of a phenotype with a genotype has been established, the latter can be reasonably suspected by a dermatopathologist familiar with the morphologic findings associated with a distinct genetic aberration. Moreover, recognizing these characteristic melanocytic tumors can help to identify BAP1 germline mutation carriers, who have an increased risk for developing various cancers, including mesothelioma and uveal and cutaneous melanoma. Affected patients may benefit from individualized management strategies and screening examinations to detect tumors in an early or premalignant state.

REPORT OF A CASE

CLINICAL FINDINGS

A 21-year-old college student was seen by one of us (M.W.) for evaluation of multiple scalp nodules present since childhood, which were continuing to enlarge and were occasionally pruritic. Nevi of the right fifth toe, right cheek, and right antihelix were also increasing in size. He had a history of atypical nevus of the chest at age 12 years. His family history was negative for atypical nevi or melanoma. Five firm dome-shaped and polypoid pink nodules (0.8-1.2 cm) were identified on the scalp (Figure 1). The right cheek and antihelix had 0.5-cm dome-shaped pink papules. The right fifth toe had a 0.4-cm medium-brown macule with a central dome-shaped papule. None of the lesions had previously been biopsied. Biopsy specimens of the scalp and fifth toe were submitted for review. Subsequently, the scalp and toe lesions were excised; a biopsy of the right ear was performed, and an additional scalp lesion was excised.

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Figure 1. Clinical findings. A, Papules on ear and cheek. B, Polypoid nodular scalp lesion. C, The right fifth toe had a 0.4-cm medium-brown macule with a central dome-shaped papule.

HISTOPATHOLOGIC FINDINGS

The lesions from the right cheek, antihelix, and scalp were compound albeit predominantly of intradermal melanocytic proliferation. All were combined lesions composed of large epithelioid melanocytes with a second minor population of small melanocytes. The nuclei of the large melanocytes were 2 to 3 times the size of the nuclei of epidermal keratinocytes and adjacent small “ordinary” melanocytes. The enlarged melanocyte nuclei had smooth nuclear contours and displayed an open chromatin pattern and distinct nucleoli.

The histopathologic findings are shown on the excisional specimen from the scalp lesion; the lesion had a polypoid nodular silhouette (Figure 2). Most of the melanocytes were large epithelioid in appearance and formed a central nodule. The small melanocytes were predominantly at the periphery but also were admixed as a minor population in the center of the lesion. There was an associated mild lymphocytic infiltrate. A few multinucleated melanocytes were present.

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Figure 2. Histopathologic findings. A, Excision of the polypoid nodule shown in Figure 1B. B, A central nodular aggregate of large epithelioid melanocytes is surrounded by aggregates of small melanocytes. The papillary dermal stroma is edematous and contains ectatic vessels and small lymphocytes. C, Large epithelioid melanocytes (thick arrows) are admixed with small epithelioid melanocytes (thin arrows). D, The large epithelioid melanocytes have round to oval nuclei with open vesicular chromatin and distinct nucleoli. They have abundant eosinophilic cytoplasm. Small lymphocytes (thin arrow) are dispersed throughout the entire lesion.

IMMUNOHISTOCHEMICAL FINDINGS

Because of the cytologic resemblance with previously seen BAP1loss/BRAFV600E melanocytic tumors,6,7 sections of the tumors were immunohistochemically analyzed for BAP1 expression. The large epithelioid melanocytes lacked nuclear labeling for BAP1 (Figure 3). In contrast, the population of small epithelioid melanocytes showed nuclear BAP1 staining. All nonlesional cells (epithelial, stromal, and inflammatory cells) were also immunoreactive for BAP1.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 3. Immunophenotype. A, A nodular proliferation of predominantly large epithelioid melanocytes with a few scattered lymphocytes is surrounded by conventional small melanocytes (arrow). B, The large melanocytes lack labeling for BAP1 expression, while the nuclei of small melanocytes (arrow) and nonmelanocytic normal cells (keratinocytes and lymphocytes) are immunoreactive (red chromogen). C, The small epithelioid melanocytes (original magnification ×200) show strong nuclear labeling for BAP1 expression (inset). D, Although lymphocytes are immunoreactive, the large epithelioid melanocytes (original magnification ×200) fail to label for BAP1 expression (inset).

MUTATIONS AND DELETIONS OF BAP1

To distinguish somatic mutations from germline mutations, BAP1 was sequenced using both a lesional tissue sample as well as the tip of a skin ellipse with no lesional melanocytes. The tumor tissue showed a BRAFV600E mutation and a frameshift mutation of BAP1 (c.214del, p.I72L*6), resulting in a truncation of the protein (Figure 4). In the sequencing electropherogram of the tumor, the signal intensity of the mutated BAP1 allele was stronger than the signal intensity of the wild-type BAP1 allele, indicating that the neoplastic cells had lost the residual wild-type BAP1 allele through a second event (eg, loss of chromosome 3, the locus of the BAP1 gene). The adjacent normal tissue showed the same BAP1 frameshift mutation and no BRAFV600E mutation. In the sequencing electropherogram of the adjacent normal tissue, the signal intensities of the mutated BAP1 allele and the wild-type BAP1 allele were equally strong, indicating that adjacent normal cells have one mutated and one wild-type BAP1 allele (heterozygous BAP1 germline mutation).

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Figure 4. Mutation analysis. BAP1 is mutated in both normal tissue (skin ellipse with no lesion) and tumor cells. Only tumor cells show the BRAFV600E mutation.

COMMENT

Several acquired mutations have been identified in melanocytic nevi and melanomas, including BRAF (common acquired nevi and superficial spreading melanoma1115), KIT (acral and mucosal melanoma, as well as melanomas on chronically sun-damaged skin16,17), HRAS (subset of Spitz nevi8,18), and GNAQ and GNA11 (blue nevi and uveal melanoma19,20). Recently, mutations and losses involving the BAP1 gene have been found in a lesion in the spectrum of atypical Spitz tumors,6,7 a heterogeneous group of melanocytic neoplasms sharing some resemblance with Spitz nevi but also displaying atypical features overlapping with melanoma. The BAP1 protein functions as a deubiquitination enzyme and is located in the nucleus. BAP1 mutations also have an important role in uveal melanoma and mesothelioma.21,22

The melanocytic tumors have a distinct histopathologic appearance and molecular profile characterized by BRAFV600E mutations and loss of BAP1 expression.6 In most cases, BAP1 loss is somatically acquired,6 but multiple tumors tend to be associated with a germline mutation of BAP1. Both sporadic tumors and melanocytic skin tumors associated with BAP1 germline mutations share the following similar distinct histopathologic features: multinucleate or giant cells, enlarged round or oval nuclei with vesicular chromatin and variably conspicuous nucleoli, and plump epithelioid cells with amphophilic cytoplasm and well-demarcated cytoplasmic borders.6,7 Furthermore, an associated lymphocytic infiltrate is commonly found.

Although limited follow-up information is available on the BAP1loss/BRAFV600E Spitz tumors, preliminary evidence suggests that most lesions are clinically indolent and likely represent combined spitzoid melanocytic nevi. However, until more long-term follow-up data are reported, conservative complete excision seems prudent for patients with an isolated individual lesion. For patients with multiple lesions, genetic counseling (including testing for germline mutations) and clinical follow-up observation is recommended, with surgical intervention when a change is noted.

Germline mutations of BAP1 predispose (with varying degrees of penetrance) to the development of various tumors, including melanocytic skin lesions, uveal and cutaneous melanoma, and mesothelioma.7,14,15,21 Although the incidence of BAP1 germline mutations in the general population is unknown, a recent study23 reported BAP1 germline mutations in 4 of 100 patients (4.0%) with ocular melanoma and in 3 of 200 patients (1.5%) with a family history of cutaneous melanoma. Although free of cancer, the patient described herein reports a family history of gastric cancer.

In conclusion, we describe the occurrence of multiple combined BAP1loss/BRAFV600E melanocytic lesions in a young man. To our knowledge, the clinical constellation of multiple papules or polypoid nodules present since childhood has not been previously reported and supports the impression of clinically indolent or benign lesions. The histopathologic features favor a combined melanocytic nevus composed of BAP1 -expressing common nevus cells and an epithelioid (spitzoid) component with loss of BAP1 expression. Finally, because genetic analysis was prompted by the knowledge of one of us (K.J.B.) about the association of distinct cytologic features with loss of BAP1 expression, the case also illustrates how phenotypic findings can lead to the diagnosis of a hereditary tumor syndrome and BAP1 germline mutations. Patients with this hereditary tumor syndrome may benefit from individualized screening and management strategies.

ARTICLE INFORMATION

Correspondence: Klaus J. Busam, MD, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (busamk@mskcc.org).

Accepted for Publication: October 3, 2012.

Author Contributions: Drs Busam, Wanna, and Wiesner had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Busam. Acquisition of data: Busam, Wanna, and Wiesner. Analysis and interpretation of data: Busam, Wanna, and Wiesner. Drafting of the manuscript: Busam, Wanna, and Wiesner. Administrative, technical, and material support: Busam. Study supervision: Busam and Wiesner.

Conflict of Interest Disclosures: None reported.

REFERENCES

Zedek DC, McCalmont TH. Spitz nevi, atypical spitzoid neoplasms, and spitzoid melanoma.  Clin Lab Med. 2011;31(2):311-320
PubMed   |  Link to Article
Scolyer RA, Murali R, McCarthy SW, Thompson JF. Histologically ambiguous (“borderline”) primary cutaneous melanocytic tumors: approaches to patient management including the roles of molecular testing and sentinel lymph node biopsy.  Arch Pathol Lab Med. 2010;134(12):1770-1777
PubMed
Miteva M, Lazova R. Spitz nevus and atypical spitzoid neoplasm.  Semin Cutan Med Surg. 2010;29(3):165-173
PubMed   |  Link to Article
Barnhill RL, Argenyi ZB, From L,  et al.  Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome.  Hum Pathol. 1999;30(5):513-520
PubMed   |  Link to Article
Busam KJ, Murali R, Pulitzer M,  et al.  Atypical spitzoid melanocytic tumors with positive sentinel lymph nodes in children and teenagers, and comparison with histologically unambiguous and lethal melanomas.  Am J Surg Pathol. 2009;33(9):1386-1395
PubMed   |  Link to Article
Wiesner T, Murali R, Fried I,  et al.  A distinct subset of atypical Spitz tumors is characterized by BRAF mutation and loss of BAP1 expression.  Am J Surg Pathol. 2012;36(6):818-830
PubMed   |  Link to Article
Wiesner T, Obenauf AC, Murali R,  et al.  Germline mutations in BAP1 predispose to melanocytic tumors.  Nat Genet. 2011;43(10):1018-1021
PubMed   |  Link to Article
Bastian BC, LeBoit PE, Pinkel D. Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features.  Am J Pathol. 2000;157(3):967-972
PubMed   |  Link to Article
Bastian BC, Wesselmann U, Pinkel D, Leboit PE. Molecular cytogenetic analysis of Spitz nevi shows clear differences to melanoma.  J Invest Dermatol. 1999;113(6):1065-1069
PubMed   |  Link to Article
Palmedo G, Hantschke M, Rütten A,  et al.  The T1796A mutation of the BRAF gene is absent in Spitz nevi.  J Cutan Pathol. 2004;31(3):266-270
PubMed   |  Link to Article
Pollock PM, Harper UL, Hansen KS,  et al.  High frequency of BRAF mutations in nevi.  Nat Genet. 2003;33(1):19-20
PubMed   |  Link to Article
Si L, Kong Y, Xu X,  et al.  Prevalence of BRAF V600E mutation in Chinese melanoma patients: large scale analysis of BRAF and NRAS mutations in a 432-case cohort.  Eur J Cancer. 2012;48(1):94-100
PubMed   |  Link to Article
Yoshikawa Y, Sato A, Tsujimura T,  et al.  Frequent inactivation of the BAP1 gene in epithelioid-type malignant mesothelioma.  Cancer Sci. 2012;103(5):868-874
PubMed   |  Link to Article
Testa JR, Cheung M, Pei J,  et al.  Germline BAP1 mutations predispose to malignant mesothelioma.  Nat Genet. 2011;43(10):1022-1025
PubMed   |  Link to Article
Bott M, Brevet M, Taylor BS,  et al.  The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma.  Nat Genet. 2011;43(7):668-672
PubMed   |  Link to Article
Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma.  J Clin Oncol. 2006;24(26):4340-4346
PubMed   |  Link to Article
Carvajal RD, Antonescu CR, Wolchok JD,  et al.  KIT as a therapeutic target in metastatic melanoma.  JAMA. 2011;305(22):2327-2334
PubMed   |  Link to Article
van Engen-van Grunsven AC, van Dijk MC, Ruiter DJ, Klaasen A, Mooi WJ, Blokx WA. HRAS-mutated Spitz tumors: a subtype of Spitz tumors with distinct features.  Am J Surg Pathol. 2010;34(10):1436-1441
PubMed   |  Link to Article
Van Raamsdonk CD, Bezrookove V, Green G,  et al.  Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi.  Nature. 2009;457(7229):599-602
PubMed   |  Link to Article
Van Raamsdonk CD, Griewank KG, Crosby MB,  et al.  Mutations in GNA11 in uveal melanoma.  N Engl J Med. 2010;363(23):2191-2199
PubMed   |  Link to Article
Abdel-Rahman MH, Pilarski R, Cebulla CM,  et al.  Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers.  J Med Genet. 2011;48(12):856-859
PubMed   |  Link to Article
Harbour JW, Onken MD, Roberson ED,  et al.  Frequent mutation of BAP1 in metastasizing uveal melanomas.  Science. 2010;330(6009):1410-1413
PubMed   |  Link to Article
Njauw CN, Kim I, Piris A,  et al.  Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families.  PLoS One. 2012;7(4):e35295http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335872/. Accessed January 11, 2013
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Clinical findings. A, Papules on ear and cheek. B, Polypoid nodular scalp lesion. C, The right fifth toe had a 0.4-cm medium-brown macule with a central dome-shaped papule.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Histopathologic findings. A, Excision of the polypoid nodule shown in Figure 1B. B, A central nodular aggregate of large epithelioid melanocytes is surrounded by aggregates of small melanocytes. The papillary dermal stroma is edematous and contains ectatic vessels and small lymphocytes. C, Large epithelioid melanocytes (thick arrows) are admixed with small epithelioid melanocytes (thin arrows). D, The large epithelioid melanocytes have round to oval nuclei with open vesicular chromatin and distinct nucleoli. They have abundant eosinophilic cytoplasm. Small lymphocytes (thin arrow) are dispersed throughout the entire lesion.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 3. Immunophenotype. A, A nodular proliferation of predominantly large epithelioid melanocytes with a few scattered lymphocytes is surrounded by conventional small melanocytes (arrow). B, The large melanocytes lack labeling for BAP1 expression, while the nuclei of small melanocytes (arrow) and nonmelanocytic normal cells (keratinocytes and lymphocytes) are immunoreactive (red chromogen). C, The small epithelioid melanocytes (original magnification ×200) show strong nuclear labeling for BAP1 expression (inset). D, Although lymphocytes are immunoreactive, the large epithelioid melanocytes (original magnification ×200) fail to label for BAP1 expression (inset).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 4. Mutation analysis. BAP1 is mutated in both normal tissue (skin ellipse with no lesion) and tumor cells. Only tumor cells show the BRAFV600E mutation.

Tables

References

Zedek DC, McCalmont TH. Spitz nevi, atypical spitzoid neoplasms, and spitzoid melanoma.  Clin Lab Med. 2011;31(2):311-320
PubMed   |  Link to Article
Scolyer RA, Murali R, McCarthy SW, Thompson JF. Histologically ambiguous (“borderline”) primary cutaneous melanocytic tumors: approaches to patient management including the roles of molecular testing and sentinel lymph node biopsy.  Arch Pathol Lab Med. 2010;134(12):1770-1777
PubMed
Miteva M, Lazova R. Spitz nevus and atypical spitzoid neoplasm.  Semin Cutan Med Surg. 2010;29(3):165-173
PubMed   |  Link to Article
Barnhill RL, Argenyi ZB, From L,  et al.  Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome.  Hum Pathol. 1999;30(5):513-520
PubMed   |  Link to Article
Busam KJ, Murali R, Pulitzer M,  et al.  Atypical spitzoid melanocytic tumors with positive sentinel lymph nodes in children and teenagers, and comparison with histologically unambiguous and lethal melanomas.  Am J Surg Pathol. 2009;33(9):1386-1395
PubMed   |  Link to Article
Wiesner T, Murali R, Fried I,  et al.  A distinct subset of atypical Spitz tumors is characterized by BRAF mutation and loss of BAP1 expression.  Am J Surg Pathol. 2012;36(6):818-830
PubMed   |  Link to Article
Wiesner T, Obenauf AC, Murali R,  et al.  Germline mutations in BAP1 predispose to melanocytic tumors.  Nat Genet. 2011;43(10):1018-1021
PubMed   |  Link to Article
Bastian BC, LeBoit PE, Pinkel D. Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features.  Am J Pathol. 2000;157(3):967-972
PubMed   |  Link to Article
Bastian BC, Wesselmann U, Pinkel D, Leboit PE. Molecular cytogenetic analysis of Spitz nevi shows clear differences to melanoma.  J Invest Dermatol. 1999;113(6):1065-1069
PubMed   |  Link to Article
Palmedo G, Hantschke M, Rütten A,  et al.  The T1796A mutation of the BRAF gene is absent in Spitz nevi.  J Cutan Pathol. 2004;31(3):266-270
PubMed   |  Link to Article
Pollock PM, Harper UL, Hansen KS,  et al.  High frequency of BRAF mutations in nevi.  Nat Genet. 2003;33(1):19-20
PubMed   |  Link to Article
Si L, Kong Y, Xu X,  et al.  Prevalence of BRAF V600E mutation in Chinese melanoma patients: large scale analysis of BRAF and NRAS mutations in a 432-case cohort.  Eur J Cancer. 2012;48(1):94-100
PubMed   |  Link to Article
Yoshikawa Y, Sato A, Tsujimura T,  et al.  Frequent inactivation of the BAP1 gene in epithelioid-type malignant mesothelioma.  Cancer Sci. 2012;103(5):868-874
PubMed   |  Link to Article
Testa JR, Cheung M, Pei J,  et al.  Germline BAP1 mutations predispose to malignant mesothelioma.  Nat Genet. 2011;43(10):1022-1025
PubMed   |  Link to Article
Bott M, Brevet M, Taylor BS,  et al.  The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma.  Nat Genet. 2011;43(7):668-672
PubMed   |  Link to Article
Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma.  J Clin Oncol. 2006;24(26):4340-4346
PubMed   |  Link to Article
Carvajal RD, Antonescu CR, Wolchok JD,  et al.  KIT as a therapeutic target in metastatic melanoma.  JAMA. 2011;305(22):2327-2334
PubMed   |  Link to Article
van Engen-van Grunsven AC, van Dijk MC, Ruiter DJ, Klaasen A, Mooi WJ, Blokx WA. HRAS-mutated Spitz tumors: a subtype of Spitz tumors with distinct features.  Am J Surg Pathol. 2010;34(10):1436-1441
PubMed   |  Link to Article
Van Raamsdonk CD, Bezrookove V, Green G,  et al.  Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi.  Nature. 2009;457(7229):599-602
PubMed   |  Link to Article
Van Raamsdonk CD, Griewank KG, Crosby MB,  et al.  Mutations in GNA11 in uveal melanoma.  N Engl J Med. 2010;363(23):2191-2199
PubMed   |  Link to Article
Abdel-Rahman MH, Pilarski R, Cebulla CM,  et al.  Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers.  J Med Genet. 2011;48(12):856-859
PubMed   |  Link to Article
Harbour JW, Onken MD, Roberson ED,  et al.  Frequent mutation of BAP1 in metastasizing uveal melanomas.  Science. 2010;330(6009):1410-1413
PubMed   |  Link to Article
Njauw CN, Kim I, Piris A,  et al.  Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families.  PLoS One. 2012;7(4):e35295http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335872/. Accessed January 11, 2013
PubMed   |  Link to Article

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